The objective of this project is to develop novel inhibitors of human papillomavirus (HPV). HPV is the cause of benign proliferation commonly referred to as warts. Genital warts are the most commonly diagnosed, viral, sexually transmitted disease and certain HPV types have been implicated as significant risk factors for the development of cervical cancer. In phase I research, antisense oligonucleotides complementary to the E2 gene of bovine papillomavirus (BPV) and HPV were identified. Oligonucleotides complementary to the E2 mRNA of BPV were found to inhibit E2 transactivation and BPV infection as measured by the focus formation assay. An oligonucleotide, ISIS 2105, was identified that inhibited HPV-11 E2 transactivation. It is the specific goal to understand the mechanism of action of ISIS 2105. A second goal is use the newly described HPV transient DNA replication assay to evaluate the antiviral potential of ISIS 2105. E2 is a transcriptional transactivator, however, recent data suggest that E2 may be a negative regulator of E6/E7 expression. A specific goal of this project is to determine the role of E2 on E6/E7 expression (positive or negative) in the context of the entire viral genome using the transient replication assay. The final objective of this project is to explore the suitability of E1 as a therapeutic target. If ISIS 2105 is found to have acceptable properties these data will be used to support the clinical development of ISIS 2105.